The Natural History of Infection

• Koch's Postulates:

  • The microorganism must be found in abundance in all organisms suffering from the disease, but should not be found in healthy organisms
  • The microorganism must be isolated from a diseased organism and grown in pure culture
  • The cultured microorganism should cause disease when introduced into a healthy organism
  • The microorganism must be re-isolated from the inoculated, diseased experimental host and identified as being identical to the original specific causative agent
• Modern Koch's Postulates (1/2):

  • A nucleic acid sequence belonging to a putative pathogen should be present in most cases of an infectious disease. Microbial nucleic acids should be found preferentially in diseased organs known, and fewer/not in those organs that lack pathology.
  • With resolution of disease, the copy number of pathogen-associated nucleic acid sequences should decrease or become undetectable. With clinical relapse, the opposite should occur.
• Modern Koch's Postulates (2/2):

  • Where sequence detection predates disease, copy number correlates with severity of disease or pathology, there is more likely to be a causal relationship
  • The nature of the microorganism should be consistent with the known biological characteristics of that group of organisms
  • These sequence-based forms of evidence for microbial causation should be reproducible
• Primary pathogens - cause disease in non-immunocompromised host:

  • Intrinsic virulence
  • Toxin production
  • Induction of abnormal host response
• Opportunistic pathogens - only cause infection in damaged host:

  • Immunosuppressed - chemotherapy, age, alcohol, infection (e.g. HIV, TB), diet
  • Tissue damage - trauma, burns, radiation
  • Catheter infections
  • Genetic defects
  • Change in host bacteria eg antibiotics, diet
• Transmission:

  • Droplet e.g. Influenza, rhinovirus, TB
  • Sexually e.g. IV, syphilis
  • Blood e.g. HBV, HIV, HCV
  • Bites - anaerobic infection, HBV, rabies
  • Faecal-oral e.g. Salmonella, norovirus
  • Environmental e.g. C dificile, strongyloides, enterovirus
  • Vector bourne through lice, ticks, fleas, sandfly, mosquitos, tsetse fly
• Attachment:

  • Adherence - the initial interaction between bacteria and host mediated through adhesins interacting with host receptors e.g. CD4 with gp120 HIV protein, Fimbria Salmonella
  • Biofilms - attachment and intracellular adhesion - Quorom Sensing
• Virulence:

  • Ability to replicate within the host
  • Toxin production - occurs in hostile environment
  • Plasmic encoded - TSST, Tetanus neurotoxin
  • Phage encoded - Cholera toxin, diptheria toxin
  • Cell death - HIV and CD4 cells, apoptosis, direct toxicity on cells by pathogen (HCV) or immune system (HBV)
  • Survival with eukaryotic cells
• Immune evasion:

  • Passive
  • Latency e.g. Herpes, malaria
  • Can hide in sanctuary sites
  • Resistance to phagocytosis and destruction by lysozymes
  • Active
  • Production of immunomodulatory proteins
  • Decoy
  • Evolution
  • Aggressive
  • Counterattack on immune system e.g. HIV
• Pathogens:

  • Bacteria
  • Viruses
  • Parasites
  • Fungal
  • Protozoa
  • Prion
• Bacteria:

  • Huge domain of single cell organisms
  • Ubiquitous in environment and with/without humans
  • Prokaryocytic - single cell simple organisms, organelles are non-membrane bound
  • Asexual replication through binary fusion
• Bacteria structure:

  • Capsule - protects it in a hostile environment
  • Cell wall - a lot of antibiotics attack this - if it's ruptured the cell will be destroyed
  • Ribosomes - key for bacteria's function; produce energy and proteins the bacterial requires
  • Plasmids - go from one bacteria to another, sending small genetic pieces of information, like antibiotic resistance
  • Flagella - helps bacterial cells to move
  • Fimbriae - proteins which attach to cells

  
• Viruses:

  • Very small infectious agents that can only replicate within cells of host organisms
  • The most abundant biological agent
  • Contain DNA or RNA and important viral proteins
• Viral structure:

  • Many viruses have a viral envelope
  • Proteins on surface are important for cell attachment
  • Have 3 or 4 proteins that are key for replication - these are what we attack with antibodies
  • Reverse transcriptase - reverse transcribes RNA to DNA
  • Integrase - integrates that DNA into the host DNA

  
• Fungal infection:

  • Eukaryotic organisms - organelles enclosed in walls
  • Yeasts (replicate through mitosis) and moulds (replicate through meiosis)
  • Cell walls contain chitin - strong
  • Septae divide cell walls and are relatively fluid

  
• Protozoa:

  • Single cell organisms
  • Very motile
  • Can engulf food
  • Often survive hostile intracellular environment
  • Asexual and sexual reproduction
  • Can encyst
  • Include: malaria, leishmaniasis, trypansomiasis
• Parasite:

  • Complex multicellular organisms
  • Symbiotic relationship
  • Often have lifecycle outside human body
  • Cause disease through direct tissue damage or immunological reaction to parasite
• Host defence:

  • Skin and membranes
  • Commensal bacteria
  • Secretions
  • Complement
  • Phagocytosis by neutrophils and macrophages
  • Cytokines
  • Innate immunity and humoral immunity
• Innate immune system (non-specific):

  • Recruitment of cells of innate immune cells through cytokines (such as histamine, prostaglandins, etc)
  • Phagocytic eg neutrophils, macrophages and dendritic cells
  • Innate cells eg mast cells, NK cells
  • Complement - opsonisation, chemoattraction direct effect against bacteria
  • Antigen presentation and activation of specialised lymphocytes
  • IgA
• Adaptive immune system:

  • Recognition of pathogens through antigen presentation
  • Specific activation of specialised cells
  • Development of 'memory' to allow quick recognition of pathogen in future

  
• T cell response:

  • TH 1 response enhance 'cell mediated immunity' - through interferon gamma. Activates macrophages. Leads to enhanced opsonisation of bacteria/viruses (often intracellular) through B cell antibody production.
  • TH 2 response 'humoral immunity' - through IL-4 leads to specific antibody production especially effective against extracellular infections and toxins.
• Immunodeficiency:

  • Caused by infection e.g. HIV
  • Poor diet/alcohol
  • Genetic e.g. complement deficiency, CGD
  • Splenic dysfunction
  • Age
  • Other diseases eg diabetes, cancer